Unlocking the Heat: How MCJ Protein Transforms Brown Fat into a Weapon Against Obesity

Obesity, which impacts 650 million individuals globally, affects the progression of cardiometabolic conditions and heightens the likelihood of cancer.

Guadalupe Sabio, head of the Organ Crosstalk in Metabolic Diseases Group at the National Cancer Research Center (CNIO), along with Cintia Folgueira, associated with CNIO and the National Center for Cardiovascular Research (CNIC), have unveiled one mechanism through which the body “burns” brown fat and transforms it into thermal energy. This process serves as a protective factor against obesity and its related metabolic disorders.

The newly identified mechanism is regulated by a protein known as MCJ, located in mitochondria (the cellular organelles responsible for energy production).

Sabio and Folgueira found that eliminating the MCJ protein from obese mice results in those animals producing greater amounts of heat and losing weight. The researchers also succeeded in decreasing the weight of obese mice merely by transplanting fat that lacked that protein.

Brown fat and obesity

“Obesity is the consequence of either excessive caloric intake or inadequate overall energy expenditure. We now understand that adipose tissue, our body’s fat, not only stores energy but also plays an essential role in managing this energy within the body. Adipose tissue functions as a complex organ that regulates the metabolism of the entire body, and thus adjusting its function may be a viable method to combat obesity,” the authors state in Nature Communications.

There are two varieties of fatty or adipose tissue: white and brown. White adipose tissue primarily stores energy, while brown fat (which contains more mitochondria giving it a brown appearance) is responsible for generating heat or thermogenesis, the mechanism that sustains body temperature and is activated by cold or other stimuli.

Numerous studies over the past decade have indicated that the activation of brown fat provides protection against obesity and metabolic ailments. “For a while,” notes Sabio, “it has been believed that preventing obesity could be achieved by encouraging this fat to expend additional energy through heat generation. Thus, the initial step is to grasp how it operates.”

“Identifying new mechanisms for heat production in brown fat represents one of the most intriguing objectives in obesity research,” asserts Sabio.

How to burn brown fat

For an extended period, it was assumed that brown fat operated via a singular mechanism to generate heat, but recent findings indicate otherwise. Multiple mechanisms are at play. The study led by Sabio and Folgueira has revealed one of these mechanisms, governed by a mitochondrial protein known as MCJ.

The investigations conducted at CNIO demonstrate that when the MCJ protein is removed from obese mice, those animals produce more heat and shed weight. Furthermore, simply transplanting brown fat devoid of the MCJ protein into the animals was sufficient to decrease their weight.

Avoiding pathologies associated with obesity

The researchers also observed that “animals lacking MCJ in brown fat are safeguarded against health issues related to obesity, such as diabetes or elevated blood lipids,” the two scientists explain. As a result, they propose that the MCJ protein might serve as a new therapeutic target to address obesity-related diseases.

“This protection,” elaborates CNIO researcher Beatriz Cicuéndez, the lead author of the study, “arises from the activation of a crucial signaling pathway that adapts to the stress induced by obesity. Known as the catabolic pathway, it facilitates an increase in the consumption of fats, sugars, and proteins to produce heat in brown fat. This mechanism also occurs in individuals with highly active brown fat.”

Blocking the MCJ protein in obese patients

The current research aims to develop a therapy to inhibit this protein in obese individuals, but first, it must determine whether the MCJ protein has critical functions in other tissues.

Simultaneously, Guadalupe Sabio mentions, “we aim to investigate whether these alterations in fat influence tumor growth or cachexia—loss of muscle and fat—which is also occasionally associated with cancer.”